New chemical transformations enable the efficient construction of important molecules that are essential for biomedical research. The most powerful and efficient chemical reactions use catalysis to control reactivity and selectivity. The developments in catalytic methodology over the last quarter century have focused primarily on established reactivity patterns, such as carbonyl additions, cycloadditions, oxidations, and reductions. Many of these reactions follow principles predicted by electronegativity concepts. Umpolung reactions invert the normal reactivity of functional groups, thereby facilitating unconventional synthetic strategies. This transformation of an electron-poor species (electrophile) into an electron-rich reactant (nucleophile) is typically accomplished using stoichiometric reagents. Even though Umpolung reactions are important in organic synthesis, there are limited catalytic polarity reversal transformations with broad scope. Our central hypothesis is new approaches to catalysis using N-heterocyclic carbenes (NHCs) can significantly advance the field of chemical methodology and health relevant chemical synthesis. The specific goals of this proposal are: (1) Explore new carbene-catalyzed homoenolate equivalent reactions. The development of innovative formal cycloadditions, silylations, and alkylations will provide direct access to a large array of bioactive structures. (2) Develop new cooperative carbene catalysis processes. We have discovered that carbenes (Lewis bases) are compatible with Lewis acids to enhance selectivity and reactivity. The combination of Lewis acid or transition metal complexes with NHCs should provide new opportunities for chemical synthesis. (3) Investigate carbene catalysis-driven total syntheses. While there has been an explosion of NHC catalyzed reactions, few target syntheses have employed any of these new reactions as a key step. We will use an NHC-catalyzed desymmetrization as the key step in the synthesis of secologanin, a key secoiridoid natural product. Additionally, we will pursue a synthesis of arnamial using our NHC-catalyzed intramolecular Michael reaction. Our research in generating new reactivity using organocatalysis will establish new approaches for the efficient synthesis of molecules. This research will also provide important knowledge about nucleophile-catalyzed polarity reversal reactions. These findings will ultimately lead to the development of a powerful collection of stereoselective and related strategies that are useful for synthesis.